Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: A randomised controlled trial Ronald Dahl a, * , Ingrid Titlestad b , Ari Lindqvist c , Pascal Wielders d , Heather Wray e , Millie Wang e , Viktoria Samuelsson f , John Mo f , Alison Holt e a Department of Respiratory Diseases, Århus University Hospital, Nørrebrogade 44, DK-8000 Århus C, Denmark b Department of Respiratory Medicine, Odense University Hospital, 5000 Odense C, Denmark c Division of Pulmonary Medicine, Helsinki University Central Hospital, PL 22 (Haartmaninkatu 4), 00014 Helsinki, Finland d Department of Pulmonary Diseases, Catharina Hospital, 5602 ZA Eindhoven, The Netherlands e AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, UK f AstraZeneca R&D Lund, Scheelevägen 2, SE-221 00 Lund, Sweden article info Article history: Received 20 April 2011 Received in revised form 5 December 2011 Accepted 30 December 2011 Keywords: COPD Matrix metalloproteinases Biomarkers Desmosine Lymphocytes abstract Background: There is a pressing need for new forms of treatment for COPD. Based on the known path- ophysiology of COPD, inhibition of matrix metalloproteinases is a theoretically promising approach. This Phase IIa study evaluated the effects of AZD1236, a selective MMP-9 and MMP-12 inhibitor, on the biomarkers of inflammation and emphysematous lung tissue degradation in patients with moderate-to- severe COPD. Methods: This was a multinational, randomized, double-blind, placebo-controlled signal-searching study conducted in men and women aged 40 years with stable moderate-to-severe COPD. After a 2e6-week period to eliminate any remaining effects of previous medication, 55 patients received oral AZD1236 75 mg or matching placebo twice daily for 6 weeks. Differential cell count and TNF-a levels in induced sputum and 24-h urinary desmosine excretion were the main study variables, but a range of exploratory biomarkers was also assessed in induced sputum, blood and urine. Secondary variables included lung function and patient-recorded Clinical COPD Questionnaire (CCQ) responses and diary records of symptoms, adverse events, use of rescue medication and AZD1236 plasma concentrations. Results: The majority of variables showed little change compared to placebo although there was a possible, but not statistically significant reduction in urinary desmosine excretion and reductions in the number and percentage of lymphocytes in sputum and blood with AZD1236. No effect was seen on clinical parameters after 6 weeks of treatment. The proportion of patients experiencing adverse events was similar in both treatment groups. Conclusions: AZD1236 dosed orally at 75 mg twice daily was generally well tolerated over 6 weeks in patients with moderate-to-severe COPD. No clinical efficacy of AZD1236 was demonstrated in this short- term signal-searching study, although possible evidence of an impact on desmosine may suggest the potential value of selective inhibitors of MMPs in the treatment of COPD in longer term trials. Ó 2012 Published by Elsevier Ltd. 1. Introduction Chronic obstructive pulmonary disease (COPD), primarily as a result of cigarette smoking, is a rapidly growing cause of morbidity and disability that already places a significant burden on healthcare systems around the world [1e5]. Both the prevalence of COPD and its age-associated mortality have increased sharply in recent decades. This has led to an increasing focus on COPD as a priority area, both for allocation of healthcare resources and for development of new therapeutic strategies, as current therapies do Abbreviations: a 1 -ATD, a 1 -antitrypsin deficiency; AE, Adverse event; CCQ, Clinical COPD Questionnaire; COPD, Chronic obstructive pulmonary disease; CRP, C- reactive Protein; FEV 1 , Forced expiratory volume in 1 s; FVC, Forced vital capacity; HCl, Hydrochloric acid; ICS, Inhaled corticosteroids; IL-1b, Interleukin-1b; IL-6, Interleukin-6; IL-8, Interleukin-8; Kco, Carbon monoxide gas transfer coefficient; LABA, Long-acting b 2 -agonist; MMP, Matrix metalloproteinase; MSS, Musculoskel- etal syndrome; PBS, Phosphate buffered saline; PDE4, Phosphodiesterase 4; PEFR, Peak expiratory flow rate; RANTES, Chemokine (C-C motif) ligand 5 (also known as CCL5); SAA, Serum Amyloid A; SABA, Short-acting b 2 -agonist; TNF-a, Tumor necrosis factor-a; TORCH, TOwards a Revolution in COPD Health study; UPLIFT, Understanding Potential Long-term Impacts on Function with Tiotropium study. * Corresponding author. Tel.: þ45 8949 2085; fax: þ45 8949 2110. E-mail address: ronadahl@rm.dk (R. Dahl). Contents lists available at SciVerse ScienceDirect Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt 1094-5539/$ e see front matter Ó 2012 Published by Elsevier Ltd. doi:10.1016/j.pupt.2011.12.011 Pulmonary Pharmacology & Therapeutics 25 (2012) 169e177